DESCRIPTION (Applicant's Description): For many years, an obstacle faced by tumor immunologists has been the failure of the immune system to respond to immune-enhancing therapeutic approaches in the setting of advanced disease. Recently, one explanation that has gained particular attention is whether antigen presented by a progressively expanding tumor cell population may result in the induction of T cell tolerance. Dr. Levitsky's laboratory has been pivotal in the development of tumor-cell based vaccines, and a major emphasis is being devoted to understand how factors mediating T cell activation versus tolerance may influence the efficacy of these strategies. In the last year, the applicants took advantage of the availability of T cell receptor (TCR) transgenic mice specific for a model tumor antigen expressed on a B cell lymphoma. Using this experimental model, they have recently shown that antigen specific CD4+ T cells are rendered tolerant during tumor progression. Moreover, these alterations in T cell function occur early in the course of the disease, suggesting that tolerance to tumor antigens may impose a significant barrier to immune-enhancing therapeutic approaches. Therefore, during the next four years it will be critical to understand the cellular and molecular basis of tumor-induced tolerance and more importantly, whether this state can be safely reverted. The knowledge to be gained in this endeavor is likely to shed light not only on the basic biology of host-tumor interactions but it also has significant clinical implications. As a medical oncologist, the applicant's ultimate goal will be to pursue the translation of these knowledge into the clinical arena where they may influence the design of the next generation of tumor immunotherapy strategies, aimed at safely breaking tolerance and potentially leading to the long elusive success of cancer immunotherapy.